Tamsulosin is a known chemical compound having alpha-adrenergic blocking activity that is useful for treatment of cardiac insufficiencies and benign prostatic hyperplasia (BPH). Tamsulosin is the common name for (R)-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxy-benzenesulfonamide. It is disclosed in EP 34432 and U.S. Pat. No. 4,731,478. Tamsulosin is a potent pharmaceutically active agent and is typically administered in amounts of less than 1 mg per day, usually 0.4 mg.
Several medicaments comprising tamsulosin, specifically tamsulosin hydrochloride, are currently marketed. The first commercially available medicament comprising tamsulosin (OMNIC, FLOMAX, marketed since 1993) were gelatin capsules filled with pellets comprising tamsulosin (0.4 mg strength). In Japan, an orally-disintegrating tablet based on WOWTAB technology (Harnal D), is also on the market.
Recently a controlled release tablet formulation was introduced on the market in Europe (Omnic OCAS, Mapelor OCAS) also containing 0.4 mg of tamsulosin hydrochloride. The tablet is purported to have less or no food effect in comparison to the capsule formulations. This marketed tablet medicament uses the so called OCAS drug delivery system which enables gradual release of a drug as the tablet travels through the digestive tract, including the colon. It appears that the relevant patent covering the OCAS delivery system is a patent family based on WO 94/06414 (EP 661045, U.S. Pat. No. 6,436,441).
In general, the OCAS system comprises a drug, a hydrogel-forming polymer and a highly water soluble hydrophilic additive (a “hydrophilic base”), which is important in aiding rapid water penetration into the core. The concept is that the preparation absorbs water as it enters and passes through the upper digestive tract such that the water-swellable polymer undergoes substantially complete gelation (i.e. at least 70%). As the preparation continues down the digestive tract, its gelled surface continues to constantly erode, thereby maintaining a release of the drug even in the lower digestive tract, e.g., in the colon.
The stability and the rate of formation of the gel layer, as well as the rate of its erosion after prolonged hydration are important factors in designing an OCAS tablet. Too little hydrophilic base can lead to insufficient gelation such that release in the colon is compromised. Too much hydrophilic base can result in a gel that is too fragile and releases the drug too rapidly and hence also compromises release in the colon. In addition to these gelation/viscosity issues, the hydrogel-forming polymer should also preferably be selected so as to provide sufficient mechanical strength so that the tablet can essentially retain its shape during its travel in spite of the contractile forces of the digestive tract.
In view of the above, the hydrogel-forming polymer which can be used in the OCAS system as the matrix-forming agent is preferably a polymer showing a high viscosity on gelation, e.g., a viscosity of not less than 1000 cps in 1% aqueous solution (at 25° C.). Because viscosity of the gel depends in part on the molecular weight, the hydrogel-forming polymer is preferably a substance having a high molecular weight of not less than 2 million and more preferably of not less than 4 million. A preferred hydrogel-forming polymer according to U.S. Pat. No. 6,436,441 is a poly(ethylene oxide), especially one having a molecular weight of not less than 2 million.
The actually marketed OCAS tablet comprising tamsulosin (or “TOCAS” tablet) comprises a high molecular weight poly(ethylene oxide) as the hydrogel-forming polymer and a polyethylene glycol as the solubility enhancing hydrophilic base. The TOCAS tablets are film coated, which coating contains hydroxypropylmethyl cellulose.
WO 2004/078212 teaches that manufacturing a tablet based on poly(ethylene oxide) with a molecular weight of 2,000,000 or higher as taught in U.S. Pat. No. 6,436,441, is difficult. For instance, the polymer becomes very sticky when exposed to moisture. Additionally, granulating the polymer turned out to be problematic. And because the intended/preferred drug, tamsulosin hydrochloride, is used in low doses, the patent publication teaches that direct compression and dry granulation are unsuited because of content uniformity concerns; e.g., the drug concentration may not be uniform throughout the tabletting blend which leads to variable dosage strengths. To address these manufacturing issues, WO 2004/078212 proposes “sizing” particles of poly(ethylene oxide) by spraying an aqueous solution or suspension of a sizing agent onto the particles and drying the particles. The sizing agent is typically a portion of the polyethylene glycol used as the hydrophilic base. Generally the drug, which is preferably tamsulosin HCl, is included in the aqueous solution/suspension of the sizing agent. The resulting poly(ethylene oxide)-containing granulate is purported to be readily incorporated into a finished dosage form such as a tablet by conventional techniques.
Another proposal for the delivery of tamsulosin throughout the whole digestive tract from a tablet formulation was disclosed in WO 2007/131804. The composition comprises a) 0.1 to 1 weight % of tamsulosin, preferably tamsulosin hydrochloride; b) 40-80 weight % of a water-swellable matrix-forming composition comprising (i) a pH-sensitive swellable hydrophilic polymer, which is a cross-linked polyacrylic acid polymer and preferably it is carbomer, and (ii) a pH-insensitive swellable hydrophilic polymer, which preferably is a linear polymer such as hydroxypropyl methylcellulose (HPMC), especially a high molecular weight HPMC; and c) optionally a water insoluble binder.
While the tablets of WO 2007/131804 exhibit a good release profile of tamsulosin, the tablet design (composition, size, shape, etc.) again requires a careful balance of properties; and achieving sufficient release in the colon is often problematic for this kind of controlled release tablet.
Obtaining controlled release throughout the digestive tract, including consistent release in the water-reduced colon, can be challenging. Obtaining such release with a low dose drug further complicates the matter as shown in the above tamsulosin tablets. It would be desirable to find a robust, easy-to-design tablet for providing low dose drugs such as tamsulosin with good drug release throughout the whole digestive tract including the colon.